In the art of pharmaceutical technology layered tablets are tablets consisting of several, firmly adhering, parallel or concentrically curved layers of compressed powder or granulate particles (cf. Hunnius Pharmazeutisches Worterbuch, 6th edition, Berlin 1986). In contrast to press-coated tablets, which are defined as tablets with a preformed core having a material completely surrounding the core and formed by compressing a powder or granular material, conventional layered tablets are manufactured in one operation and in a tablet press by repeatedly compressing different kinds of particles, the layers obtaining a characteristic form owing to the fact that the same press is used in each compression. For this reason, the forms of the individual layers cannot be chosen freely, i.e., independently of each other. The use of biplanar punches results in layered tablets having consistently parallel layers, except for the border areas in the region of the optional facet. If curved punches are used, the lower layer, which is pressed first, assumes a biconvex shape, whereas the upper or second layer has a uniform thickness and is parallel with the curved upper boundary surface of the layer pressed first.
In 1917, layered tablets and a process for their production were described for the first time (U.S. Pat. No. 1,248,571). They are used in pharmacy for several considerations. On the one hand, they offer the possibility of combining incompatible active substances in one tablet in a spatially separated form. On the other hand, they permit combination of several formulations having different release properties. For instance, the one layer may be used to release an initial dose of the active substance in the form of a fast-disintegrating, quick-releasing formulation, whereas the second layer comprises a maintenance dose in retarded form.
Quite recently, special layered tablets for the controlled release of active substances, in particular for zero-order release, have been described (U. Conte et al., J. Controlled Rel. 26, pp. 39-47, 1993). These layered tablets comprise an active substance-containing swelling matrix and at least one excipient ingredient layer pressed thereon and covering the matrix surface on one side. The layer of inactive ingredients is substantially inert and impermeable to active substances. The active substance-containing matrix releases the active substance in liquid media by means of diffusion.
Swelling of the matrix in aqueous medium is intended to ensure that the release rate does not decrease in the course of substance release--owing to progressive active substance depletion of the matrix and simultaneous extension of the diffusion path, but is maintained in terms of a zero-order process. This swelling causes a substantial enlargement of the matrix surface as compared to its dry state. However, the published data relating to the actual release behavior of these layered tablets show that the swelling effect in most practical cases is not sufficient to maintain the initial release rate. If, on the other hand, the swelling matrix is formulated such that it swells in an aqueous medium to an extreme extent, insufficient cohesion of the tablet is nearly inevitable: it disintegrates and thereby results in "dose dumping", i.e., a sudden release of the remaining active substance.
In administration forms other than layered tablets, the design principle of continuously enlarging a matrix' contact surface to the liquid release medium to control the release rate has been realized in a different manner. WO 94/0747 describes, at least basically, the use of an envelope having a thickness differing at several sites and consisting of a material which is erodable in a liquid medium; this envelope is designed for devices belonging to the type of coated solid drugs (coated tablets and capsules) produced by conventional coating or film-coating methods. During the release of active substance, the envelope erodes; this process is terminated at the thinnest sites of the envelope first, and it proceeds in a continuous or discontinuous manner. The superficial expansion of the envelope decreases, whereas the contact surface of the core to the release medium increases.
WO 94/0747 describes tablets covered with a coating. However, it does not show a possible selective production of the thickness gradients of the coating which are required to utilize the effect of boundary enlargement. The conventional coating methods, which are mentioned as production method, inevitably result in slightly non-uniform thicknesses with certain core shapes. For example, when tablets or capsules are coated, it cannot be prevented that the film thickness is below average at the edges and at sites having a small radius of curvature. In examples 1 and 4, the conventional coating methods are not even varied to obtain a non-uniform thickness. Moreover, it is not to be expected that these coating methods (fluidized bed and coating pan methods are mentioned) can be performed such that the thickness gradients of the erodable envelope, which are necessary for a continuous surface enlargement of the core, can be formed in a selective manner.
In view of the lack of suitable manufacturing methods for such administration forms with erodable coatings having thickness gradients, there is a need of alternative solutions which are no longer based on the design principle comprising a core and a coating. German patent application P 43 41 442.7 already teaches, although mainly with reference to the Figures, that thickness gradients to obtain the above-mentioned effect can also be realized by arranging the administration form in approximately parallel layers; however, there are no indications with respect to a preferred embodiment, for example, in the form of a coextruded article or several pressed pieces which are glued together. If pressed articles are used for the active substance-containing matrix or for the erodable excipient layer, there is no useful indication with respect to production engineering, except for the fact that an adhesion-promoting auxiliary material should be used, if the layers do not adhere to each other by themselves, i.e., which kind of suitable production method or design of device should be used to allow an efficient combination or joining of the pressed pieces to form an administration form, as in the case of a layered tablet, for example.